A closer look at rituximab induction on HLA antibody rebound following HLA-incompatible kidney transplantation

Abstract

Rituximab has been used to increase the efficacy of desensitization protocols for human leukocyte antigen (HLA)-incompatible kidney transplantation; however, controlled comparisons have not been reported. Here we examined 256 post-transplant HLA antibody levels in 25 recipients desensitized with and 25 without rituximab induction, to determine the impact of B-cell depletion. We found significantly less HLA antibody rebound in the rituximab-treated patients (7% of donor-specific antibodies (DSAs) and 33% of non-DSAs) compared with a control cohort desensitized and transplanted without rituximab (32% DSAs and 55% non-DSAs). The magnitude of the increase was significantly larger among patients who did not receive rituximab. Interestingly, in rituximab-treated patients, of the 39 HLA antibodies that increased post transplant, 34 were specific for HLA mismatches present in previous allografts or pregnancies, implying limited efficacy in memory B-cell depletion. Compared with controls, rituximab-treated patients had a significantly greater mean reduction in DSA (-2505 vs. -292 mean fluorescence intensity), but a similar rate of DSA persistence (52% in rituximab treated-and 40% in non-treated recipients). Thus, rituximab induction in HLA-incompatible recipients reduced the incidence and magnitude of HLA antibody rebound, but did not affect DSA elimination, antibody-mediated rejection, or 5-year allograft survival when compared with recipients desensitized and transplanted without rituximab.

Figure 1. HLA antibody rebound following HLA-incompatible transplantation: decreased incidence and magnitude in recipients receiving rituximab induction

HLA antibodies (54 DSA and 202 non-DSA) were measured prior to desensitization (time 0) and at four post-transplant time points (1, 3, 6, 12 months) in patients transplanted with or without rituximab induction. MFI values were normalized to the positive control bead and percent change from time zero was plotted. The incidence of post-transplant DSA (p = 0.03) and non-DSA class I and class II HLA antibody (p= 0.0027) rebound and the magnitude of the antibody rebound (p=0.02) were lower in patients transplanted with rituximab induction compared to those without induction.

Figure 2. Rituximab induction reduces donor-specific (DSA) and non-DSA HLA antibody strength and incidence of rebound post-transplantation

The change in pre-treatment MFI and peak post-transplant MFI for donor-specific (DSA) and non-DSA HLA antibodies were compared between patients transplanted with or without rituximab induction. Values plotted above dotted line represent a post-transplant antibody rebound above pre-treatment levels. The mean MFI change for DSA (−2505 versus −292, p= 0.006) and for non-DSA HLA antibodies (−309 versus +1938, p= 0.0006) are denoted by solid lines and were statistically lower in patients transplanted with rituximab induction.

Figure 3. Post-transplantation HLA antibody rebound reflects previous HLA antigen mismatches but not pre-transplantation baseline HLA antibody strength

HLA phenotypes for the recipient and three renal allografts are provided. This patient received rituximab induction and experienced rebounds in non-DSA HLA antibodies but no increase in DSA directed toward the current (3rd) allograft. MFI values for HLA antibodies detected prior to desensitization and one month following the 3rd transplantation are shown. All HLA antibodies specific for previous HLA mismatches are shown and the asterisk highlights antibody reactivity toward a known cross-reactive epitope in a previous mismatched antigen (HLA-A1 and HLA-A24).

Figure 4. Mortality and death-censored graft loss in the rituximab treated vs. non-rituximab treated cohorts

Kaplan–Meier estimates of (A) patient 1 and 5-year survival were 96.0% (95% CI: 74.8–99.4%) and 81.7% (95% CI: 51.9–94.0%) in the rituximab treated group and 96.0% (95% CI: 74.8–99.4%) and 83.7% (95% CI: 56.3–94.6%) in the non-rituximab treated group (P=0.6) (B) graft 1 and 5-year death-censored survival were 100.0% and 94.7% (95% CI: 68.0–99.0%) in the rituximab treated group and 95.8% (95% CI: 73.9–99.4%) and 77.5% (95% CI: 49.7–91.1%) in the non-rituximab treated group (P=0.23).